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Management of Peptic ulcer disease

Dr. Bushra Hasan KhanJunior Resident-1,

Department Of Pharmacology,JNMC,AMU,Aligarh.

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CONTENTS

Physiology of Gastric acid secretion

An introduction to Peptic Ulcer Disease

Drugs used in PUD

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PHYSIOLOGY OF GASTRIC ACID SECRETION

• Food is broken into macroparticles

• Acid causes hydrolysis,

sterilizes the meal content

& activates pepsinogen to pepsin

• Acid secretion:

• Basal

• Stimulated

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DIAGRAM SHOWING OXYNTIC GASTRIC GLAND

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GASTRIC PARIETAL CELL UNDERGOING

TRANSFORMATION AFTER SECRETAGOGUE MEDIATED

STIMULATION

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PHASES OF GASTRIC ACID SECRETION AND THEIR

REGULATION

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PATHOPHYSIOLOGY

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PHYSIOLOGICAL REGULATION OF GASTRIC ACID SECRETION

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HCL

GASTRINHISTAMINE

ACETYLCHOLINE

ECL

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PEPTIC ULCER DISEASE

•PEPTIC ULCER is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation.

Epidemiology

• Middle-age to older age .

• peptic ulcers - first portion of the duodenum or in the stomach, in a ratio of about 4:1.

•Male/female ratio is 3:1

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PEPTIC ULCER DISEASE

IMBALANCE

FACTORS THAT

PROTECT AGAINST ACIDITY

FACTORS THAT

INCREASE ACID

SECRETION

AcidPepsin Bile acidsNSAIDsH. pylori AlcoholPancreatic

enzymes

Mucusbicarbonate layerBlood flowcell renewalProstaglandinsTight junction b/w epithelium

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CLINICAL PRESENTATION

• Epigastric pain

• Burning, aching, gnawing, hunger pain

aggravated by food in Gastric ulcer ,

relieved by food in Duodenal ulcer

• Bloating and nausea

• Loss of appetite and weight loss in Gastric ulcer

• In Severe Cases

- Vomiting blood or coffee ground like material

- Black tarry stools

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CLASSIFICATION OF ANTI-ULCER DRUGS

1.Drugs for reduction of acid secretion: Proton Pump Inhibitors:

Omeprazole , Lansoprozole, Dexlansoprazole , Pantoprozole , Rabeprozole, Esomeprozole

H2 receptor antagonists:

Ranitidine, Famotidine, Cimetidine ,Roxatidine

Anticholinergics: Pirenzepine, Propantheline ,Oxyphenonium

Prostaglandin analogues: Misoprostol

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2.Drugs to neutralize gastric acid (antacids):

Nonsystemic:-

Aluminium hydroxide , Mag. hydroxide

Magaldrate , Mag. trisilicate ,

Calcium carbonate .

Systemic:-

Sodium bicarbonate ,

Sodium citrate

MISCELLANEOUS ADJUVANTS-

Simethicone

Sodium alginate

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3.Ulcer Protectives: •Sucralfate, •Colloidal Bismuth Subcitrate and Bismuth Subsalicylate•Ranitidine bismuth citrate

Newer cytoprotectives- Rebamipide,Ecabet

4.Antimicrobial drugs for H. pylori eradication: • Amoxycillin •Clarithromycin•Metronidazole•Tinidazole •Tetracycline

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PHYSIOLOGICAL AND PHARMACOLOGICAL REGULATION OF GASTRIC ACID SECRETION

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PROTON PUMP INHIBITORS

• Diminish daily acid production (basal and stimulated) by 80-95%

• Absorbed from small intestine at a pH of 6

• PPIs are prodrugs - acidic environment needed for activation.

•MECHANISM OF ACTION

• After absorption prodrug gets activated to a tetracyclic sulfenamide cation .

• Activated form then binds covalently with sulfhydryl groups of cysteines in the H+, K+-ATPase, irreversibly inactivating the pump molecule.

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•Maximum acid inhibitory effect between

2 and 6 hours after administration and

duration of inhibition lasting up to 72–96 hours.

•Because the pumps need to be activated for these

agents to be effective, their efficacy is maximized if

they are administered before meal.

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DOSAGE OF PPIs :

•Omeprazole 20 mg OD

•Esomeprazole 20 - 40 mg OD

•Rabeprazole 20 mg OD

• Lansoprazole 30 mg OD

•Pantoprazole 40 mg OD

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PPIs: ADRs• Nausea, Diarrhea, Abdominal pain, Flatulence.•Nosocomial pneumonia• Clostridium difficle diarrhoea•Hypergastrinemia, REBOUND hypersecretion of acid•Arthralgia, headache, skin rashes.

•Drug interactions :Decreased acidity may decrease the absorption of

Ketoconazole, Ampicillin esters, Iron salts, DigoxinCYP2C19 and CYP3A4 enz inhibition metabolism of benzodiazepines, warfarin, phenytoin,

diazepam, theophylline etc

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H2 RECEPTOR ANTAGONISTS

• Inhibit acid production by reversibly competing with

histamine for binding to H2 receptors on the basolateral

membrane of parietal cells.

•Suppress acid production by 70%

• Inhibit basal and stimulated acid secretion, which

accounts for their efficacy in suppressing nocturnal acid

secretion.

•Ranitidine, Famotidine, Roxatidine, Nizatidine.

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Adverse Drug Reactions of H2 antagonists

•Diarrhea, headache, drowsiness, fatigue, muscular

pain, and constipation.

•Confusion, delirium, hallucinations, slurred speech

•REBOUND hyperacidity

•Pancytopenia, neutropenia, anemia, and

thrombocytopenia

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Dose of H2 antagonists

Ranitidine 300 mg hs

Famotidine 40 mg hs

Nizatidine 300 mg hs

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PROSTGLANDIN ANALOGUES

MISOPROSTOL- PGE1 ANALOGUE•MOA- Binds to EP3 receptor on parietal cells and

stimulate Gi pathway- thereby decreasing intracellular cAMP &

gastric acid secretion.

•Cytoprotective effects

Daily dose –•The usual recommended dose for ulcer prophylaxis is 200 micrograms four times a day.

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Pharmacokinetics

• Inhibit acid sec.in 30 min.,peaks at 60-90 min.,lasts for

3 hrs.

Adverse effects

•Diarrhea

•Exacerbations of IBD

•C/I in pregnancy as increases uterine motility

Therapeutic Use- prophylaxis of NSAIDs induced

ulcers

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ANTICHOLINERGICS (rarely used now)

SELECTIVE M1 BLOCKERS-PIRENZEPINE,TELENZEPINE

The ACh receptor on the parietal cell is of the M3 subtype.

Suppress neural stimulation of acid production via actions on

M1 receptors of intramural ganglia.

Poor efficacy, significant and undesirable anticholinergic side

effects, and risk of blood disorders (pirenzepine)

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ANTACIDS•ALUMINIUM HYDROXIDE, MAGNESIUM HYDROXIDE,

MAGNESIUM TRISILICATE, CALIUM CARBONATE,

MAGALDRATE

•MOA-neutralises HCL and form AlCl3 and MgCl2 &

Carbonates

•Fixed combinations of magnesium and aluminum

(Al3+ can relax gastric smooth muscle, producing delayed

gastric emptying and constipation; Mg2+ causes loose

stools).

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•The magnesium-containing preparations :

contraindicated in chronic renal failure patients

because of possible hypermagnesemia.

• Aluminum causes chronic neurotoxicity.

( Calcium Carbonate and Sodium Bicarbonate rarely

used now a days.)

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DRUG INTERACTIONS

•Aluminium and Magnesium ions form inert complexes-

Tetracyclines, Fluoroquinlones, Itraconazole, Digoxin or

Iron salts

•Aluminium group of antacids decrease the

bioavailability of Phosphates, Iron salts and Digoxin

•By raising gastric pH and ionization, antacids decrease

the absorption of acidic drugs- Barbiturates, Phenytoin,

NSAIDS .

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SIMETHICONE

•Silicon polymer, reduces flatulence and hiccups

•Surfactant,antifoaming agent, cause proper dispersal

of antacid over gastric surface , coats ulcer base.

SODIUM ALGINATE-

•Hydrophilic colloidal carbohydrate derived from

seaweeds

•Used with antacid & H2 antagonist-heart burn & GERD

• It forms viscous gel with gastric acid-floats at top of

gastric contentact as a mechanical barrier to gastric

reflux

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ULCER PROTECTIVES

• SUCRALFATE-

•Complex sucrose salt - the hydroxyl groups substituted

by aluminum hydroxide and sulfate.

•MOA:

Enhances prostaglandin synthesis,

Stimulates mucus and bicarbonate secretion, and

Enhances mucosal defense and repair.

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Dose:

• 1 g four times daily (for active duodenal ulcer)

•1 g twice daily (for maintenance therapy)

SIDE EFFECTS

•Constipation

•Avoided in pts. with chronic renal insufficiency to

prevent aluminum-induced neurotoxicity

•The "sticky" nature of the viscous gel - bezoars in

some patients with underlying gastroparesis.

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COLLOIDAL BISMUTH SUBCITRATE &

BISMUTH SUBSALICYLATE

• In acidic media CBS- forms acid resistant protective coating

over ulcer base

• Also stimulates mucosal PGE2 synthesis & HCO3- secretion

• Dislodges H.PYLORI from gastric mucosa –antimicrobial activity.

• Dose: 120 mg qid

• Heals ulcer in 4 – 8 wks

• ADRs- blackening of stool,darkening of tongue

• Prolonged use –Neuropathy,osteodystrophy, encephalopathy.

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Anti H.pylori drugs • Helicobacter pylori: gram negative bacillus

• Attaches to gastric epithelium:

gastritis, dyspepsia, peptic ulcer, gastric lymphoma, gastric

carcinoma.

• No single agent is effective in eradicating the organism.

• Combination therapy for 14 days provides the greatest efficacy

• The agents used with the greatest frequency include

amoxicillin, metronidazole, tetracycline, clarithromycin, and

bismuth compounds.

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• Choice of a particular regimen will be influenced by -

Efficacy,

Patient tolerance,

Existing antibiotic resistance,

Cost of the drugs

• Two anti-H. pylori regimens available in prepackaged formulation:

Prevpac (lansoprazole, clarithromycin, and amoxicillin)

The contents taken twice per day for 14 days

Helidac (BSS, tetracycline, and metronidazole).

Helidac constituents taken four times per day with an

antisecretory agent (PPI or H2 blocker), also for at least 14 days.

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TRIPLE THERAPY

The BEST among all the Triple therapy regimens is

Omeprazole / Lansoprazole - 20 / 30 mg BD

Clarithromycin - 500 mg BD

Amoxycillin - 1gm BD

Given for 14 days followed by P.P.I for 4 – 6 weeks

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QUADRUPLE THERAPY

GIVEN WHEN TRIPLE THERAPY FAILS

Omeprazole/lansoprazole - 20 / 30 mg OD

Bismuth subsalycilate - 525 mg

Metronidazole - 250 mg QID

Tetracycline - 500 mg QID

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SEQUENTIAL THERAPY (10 DAYS)

For 1-5 days

• Omeprazole /lansoprazole -20 mg/30mg BD

• Amoxicillin -1 g BD

Followed by 6-10 days

• Omeprazole/lansoprazole -20mg/30mg BD

• Clarithromycin -500 mg BD

• Tinidazole -500 mg BD

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Major SIDE EFFECTS of drugs

•Bismuth : black stools, constipation, or darkening

of the tongue.

• Amoxicillin : nausea, vomiting, skin rash,

allergic reaction , pseudomembranous colitis ,

antibiotic-associated diarrhea.

• Tetracycline : rashes and, very rarely,

hepatotoxicity and anaphylaxis.

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Treatment of patients infected with

resistant strains of H.pylori•Regimens considered for second-line therapy include:

•Combi. of Pantoprazole, Amoxicillin, and Rifabutin for 10 days (86% cure rate)

• Levofloxacin-based triple therapy (Levofloxacin, Amoxicillin, PPI) for 10 days .

• furazolidone-based triple therapy (Furazolidone, Amoxicillin, PPI) for 14 days.

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THANK YOU